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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Accelerated development of pulmonary fibrosis via Cu,Zn-superoxide dismutase-induced alternative activation of macrophages.

Authors: He, Chao; Ryan, Alan J; Murthy, Shubha; Carter, A Brent

Published In J Biol Chem, (2013 Jul 12)

Abstract: Macrophages not only initiate and accentuate inflammation after tissue injury, but they are also involved in resolution and repair. This difference in macrophage activity is the result of a differentiation process to either M1 or M2 phenotypes. M1 macrophages are pro-inflammatory and have microbicidal and tumoricidal activity, whereas the M2 macrophages are involved in tumor progression and tissue remodeling and can be profibrotic in certain conditions. Because mitochondrial Cu,Zn-superoxide dismutase (Cu,Zn-SOD)-mediated H2O2 is crucial for development of pulmonary fibrosis, we hypothesized that Cu,Zn-SOD modulated the macrophage phenotype. In this study, we demonstrate that Cu,Zn-SOD polarized macrophages to an M2 phenotype, and Cu,Zn-SOD-mediated H2O2 levels modulated M2 gene expression at the transcriptional level by redox regulation of a critical cysteine in STAT6. Furthermore, overexpression of Cu,Zn-SOD in mice resulted in a profibrotic environment and accelerated the development of pulmonary fibrosis, whereas polarization of macrophages to the M1 phenotype attenuated pulmonary fibrosis. Taken together, these observations provide a novel mechanism of Cu,Zn-SOD-mediated and Th2-independent M2 polarization and provide a potential therapeutic target for attenuating the accelerated development of pulmonary fibrosis.

PubMed ID: 23720777 Exiting the NIEHS site

MeSH Terms: Adolescent; Adult; Animals; Cell Line; Cell Polarity/genetics; Cytokines/genetics; Cytokines/metabolism; Disease Progression; Gene Expression; Humans; Hydrogen Peroxide/metabolism; Immunoblotting; Macrophage Activation/genetics*; Macrophages, Alveolar/classification; Macrophages, Alveolar/enzymology; Macrophages, Alveolar/metabolism; Macrophages/classification; Macrophages/enzymology; Macrophages/metabolism*; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Middle Aged; Mitochondria/enzymology; Mitochondria/genetics; Mitochondria/metabolism; Pulmonary Fibrosis/genetics; Pulmonary Fibrosis/metabolism*; Pulmonary Fibrosis/pathology; Reverse Transcriptase Polymerase Chain Reaction; Superoxide Dismutase/genetics; Superoxide Dismutase/metabolism*; Th2 Cells/metabolism; Young Adult

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